Endothelin-1 impairs alveolar epithelial function via endothelial ETB receptor.
BACKGROUND
Endothelin-1 (ET-1) is increased in patients with high-altitude pulmonary edema and acute respiratory distress syndrome, and these patients have decreased alveolar fluid reabsorption (AFR).


OBJECTIVE
To determine whether ET-1 impairs AFR via activation of endothelial cells and nitric oxide (NO) generation.


METHODS
Isolated perfused rat lung, transgenic rats deficient in ETB receptors, coincubation of lung human microvascular endothelial cells (HMVEC-L) with rat alveolar epithelial type II cells or A549 cells, ouabain-sensitive 86Rb+ uptake.


RESULTS
The ET-1-induced decrease in AFR was prevented by blocking the endothelin receptor ETB, but not ETA. Endothelial-epithelial cell interaction is required, as direct exposure of alveolar epithelial cells (AECs) to ET-1 did not affect Na,K-ATPase function or protein abundance at the plasma membrane, whereas coincubation of HMVEC-L and AECs with ET-1 decreased Na,K-ATPase activity and protein abundance at the plasma membrane. Exposing transgenic rats deficient in ETB receptors in the pulmonary vasculature (ET-B(-/-)) to ET-1 did not decrease AFR or Na,K-ATPase protein abundance at the plasma membrane of AECs. Exposing HMVEC-L to ET-1 led to increased NO, and the ET-1-induced down-regulation of Na,K-ATPase was prevented by the NO synthase inhibitor l-NAME, but not by a guanylate cyclase inhibitor.


CONCLUSIONS
We provide the first evidence that ET-1, via an endothelial-epithelial interaction, leads to decreased AFR by a mechanism involving activation of endothelial ETB receptors and NO generation leading to alveolar epithelial Na,K-ATPase down-regulation in a cGMP-independent manner.
Comellas
Alejandro P
AP
Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA. alejandro-comellas@uiowa.edu
Briva
Arturo
A
Dada
Laura A
LA
Butti
Maria L
ML
Trejo
Humberto E
HE
Yshii
Cecilia
C
Azzam
Zaher S
ZS
Litvan
Juan
J
Chen
Jiwang
J
Lecuona
Emilia
E
Pesce
Liuska M
LM
Yanagisawa
Masashi
M
Sznajder
Jacob I
JI
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D006152:Cyclic GMP / Q000378:metabolism; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000378:metabolism*; D015633:Extravascular Lung Water / Q000378:metabolism*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D055370:Lung Injury / Q000378:metabolism; D008297:Male; D009569:Nitric Oxide / Q000096:biosynthesis*; D011650:Pulmonary Alveoli / Q000378:metabolism*; D051381:Rats; D055647:Rats, Transgenic; D044022:Receptor, Endothelin A / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000378:metabolism*; D012128:Respiratory Distress Syndrome / Q000378:metabolism
D019332:Endothelin-1; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D009569:Nitric Oxide; D000251:Adenosine Triphosphatases; D006152:Cyclic GMP